Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture

被引:42
作者
Donahue, Daniel A. [1 ,2 ]
Sloan, Richard D. [1 ]
Kuhl, Bjoern D. [1 ,3 ]
Bar-Magen, Tamara [1 ]
Schader, Susan M. [1 ,2 ]
Wainberg, Mark A. [1 ,2 ,3 ]
机构
[1] McGill Univ, AIDS Ctr, Lady Davis Inst Med Res, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3T 1E2, Canada
[3] McGill Univ, Dept Expt Med, Montreal, PQ H3T 1E2, Canada
基金
加拿大健康研究院;
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; TREATMENT-NAIVE PATIENTS; CD4(+) T-CELLS; COMBINATION THERAPY; INTEGRASE INHIBITOR; IN-VIVO; REVERSE TRANSCRIPTION; LIFELONG PERSISTENCE; VIRAL RESERVOIRS; EXTENDED PERIODS;
D O I
10.1128/AAC.01537-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Recent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data provide in vitro evidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.
引用
收藏
页码:1047 / 1054
页数:8
相关论文
共 45 条
[1]   PRODUCTION OF ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED RETROVIRUS IN HUMAN AND NONHUMAN CELLS TRANSFECTED WITH AN INFECTIOUS MOLECULAR CLONE [J].
ADACHI, A ;
GENDELMAN, HE ;
KOENIG, S ;
FOLKS, T ;
WILLEY, R ;
RABSON, A ;
MARTIN, MA .
JOURNAL OF VIROLOGY, 1986, 59 (02) :284-291
[2]   Cellular Reservoirs of HIV-1 and their Role in Viral Persistence [J].
Alexaki, Aikaterini ;
Liu, Yujie ;
Wigdahl, Brian .
CURRENT HIV RESEARCH, 2008, 6 (05) :388-400
[3]   Characterization of the early steps of infection of primary blood monocytes by human immunodeficiency virus type 1 [J].
Arfi, Vanessa ;
Riviere, Lise ;
Jarrosson-Wuilleme, Loraine ;
Goujon, Caroline ;
Rigal, Dontinique ;
Darlix, Jean-Luc ;
Cimarelli, Andrea .
JOURNAL OF VIROLOGY, 2008, 82 (13) :6557-6565
[4]   HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing? [J].
Arnaout, RA ;
Nowak, MA ;
Wodarz, D .
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2000, 267 (1450) :1347-1354
[5]   The challenge of viral reservoirs in HIV-1 infection [J].
Blankson, JN ;
Persaud, D ;
Siliciano, RF .
ANNUAL REVIEW OF MEDICINE, 2002, 53 :557-593
[6]   Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection [J].
Cavert, W ;
Notermans, DW ;
Staskus, K ;
Wietgrefe, SW ;
Zupancic, M ;
Gebhard, K ;
Henry, K ;
Zhang, ZQ ;
Mills, R ;
McDade, H ;
Goudsmit, J ;
Danner, SA ;
Haase, AT .
SCIENCE, 1997, 276 (5314) :960-964
[7]   Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: Implications for eradication of virus [J].
Chun, Tae-Wook ;
Justement, J. Shawn ;
Moir, Susan ;
Hallahan, Claire W. ;
Maenza, Janine ;
Mullins, James I. ;
Collier, Ann C. ;
Corey, Lawrence ;
Fauci, Anthony S. .
JOURNAL OF INFECTIOUS DISEASES, 2007, 195 (12) :1762-1764
[8]   HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir [J].
Chun, TW ;
Nickle, DC ;
Justement, JS ;
Large, D ;
Semerjian, A ;
Curlin, ME ;
O'Shea, MA ;
Hallahan, CW ;
Daucher, M ;
Ward, DJ ;
Moir, S ;
Mullins, JI ;
Kovacs, C ;
Fauci, AS .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (11) :3250-3255
[9]   HIV interactions with monocytes and dendritic cells: viral latency and reservoirs [J].
Coleman, Christopher M. ;
Wu, Li .
RETROVIROLOGY, 2009, 6
[10]   Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy [J].
Dinoso, J. B. ;
Kim, S. Y. ;
Wiegand, A. M. ;
Palmer, S. E. ;
Gange, S. J. ;
Cranmer, L. ;
O'Shea, A. ;
Callender, M. ;
Spivak, A. ;
Brennan, T. ;
Kearney, M. F. ;
Proschan, M. A. ;
Mican, J. M. ;
Rehm, C. A. ;
Coffin, J. M. ;
Mellors, J. W. ;
Siliciano, R. F. ;
Maldarelli, F. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9403-9408